Profiling the heterogeneity of colorectal cancer consensus molecular subtypes using spatial transcriptomics

Abstract

The consensus molecular subtypes (CMS) of colorectal cancer (CRC) is the most widely-used gene expression-based classification and has contributed to a better understanding of disease heterogeneity and prognosis. Nevertheless, CMS intratumoral heterogeneity restricts its clinical application, stressing the necessity of further characterizing the composition and architecture of CRC. Here, we used Spatial Transcriptomics (ST) in combination with single-cell RNA sequencing (scRNA-seq) to decipher the spatially resolved cellular and molecular composition of CRC. In addition to mapping the intratumoral heterogeneity of CMS and their microenvironment, we identified cell communication events in the tumor-stroma interface of CMS2 carcinomas. This includes tumor growth-inhibiting as well as -activating signals, such as the potential regulation of the ETV4 transcriptional activity by DCN or the PLAU-PLAUR ligand-receptor interaction. Our study illustrates the potential of ST to resolve CRC molecular heterogeneity and thereby help advance personalized therapy.

Tumor-agnostic transcriptome-based classifier identifies spatial infiltration patterns of CD8+T cells in the tumor microenvironment and predicts clinical outcome in early-phase and late-phase clinical trials

“…Among desert-enriched genes, we retrieved the glucose transported GLUT10 (encoded by SLC2A10) and the Wnt pathway inhibitor NKD1, which showed preferential expression in tumor cells and fibroblasts (figure 5B-D and online supplemental figure S6B). By using publicly available spatial transcriptomics data in CRC (Valdeolivas et al 46 and Wu et al 2022 45 ), we confirmed an enrichment in NKD1 expression in CD8-desert as compared with CD8high tumor areas. In addition, we observed the strongest expression of LAMP5 in the sample showing CD8 infiltration in the stromal area only, in line with LAMP5 being excluded-enriched (online supplemental figure S6C).…”

“… 35 To explore the spatial distributions of individual genes, publicly available 10×Visium data from CRC 45 were reprocessed as described previously. 46 …”

Advances in Precision Medicine Approaches for Colorectal Cancer: From Molecular Profiling to Targeted Therapies

“…Standardization of modeling methodologies, validation of predictive algorithms, and addressing the dynamic nature of tumor biology remain critical hurdles. Collaborative efforts between computational scientists, bioinformaticians, and experimental researchers are essential to bridge the gap between computational predictions and experimental validations, ensuring the reliability and reproducibility of precision nanomedicine strategies. , …”

“…Collaborative efforts between computational scientists, bioinformaticians, and experimental researchers are essential to bridge the gap between computational predictions and experimental validations, ensuring the reliability and reproducibility of precision nanomedicine strategies. 233,234…”